Alcoholic fatty liver disease (AFLD) is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. During the last grant period, we and several other groups have discovered that the development of AFLD in several rodent models is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. While the role of adiponectin and its hepatic signaling has been firmly established in the development of AFLD, the cellular and molecular mechanisms whereby ethanol inhibits the expression and production of adiponectin in adipose tissue and impairs adiponectin-mediated signaling in liver remain largely unknown. Therefore, this current competitive renewal proposal focuses specifically and exclusively on the molecular mechanisms of ethanol-induced inhibition of adipose adiponectin expression and impairment of hepatic adiponectin signaling by examining novel and exciting hypotheses that two important adipose transcriptional regulators, FoxO1 and Lipin-1, may be involved in ethanol-dependent regulation of adiponectin, and that the inhibitory effect of ethanol on adiponectin via these two molecules may result partially from ethanol inhibition of SIRT1, an NAD(+)-dependent class III protein deacetylase, and more generally, SIRT1 may represent a central target for the action of adiponectin and ethanol both in the adipose tissue and in the liver. The Specific Aims of the proposal are to: 1) Investigate the roles of FoxO1, Lipin-1 and SIRT1 in ethanol-mediated down regulation of adiponectin in mouse adipose tissue; 2) Identify underlying mechanisms by which ethanol impairs the SIRT1-adiponectin axis via FoxO1 or Lipin-1 in cultured adipocytes; 3) Investigate the mechanisms through which ethanol impairs hepatic adiponectin-SIRT1 signaling. We will utilize state-of-the-art molecular, cellular and biochemical approaches with cell culture and animal models to dissect the signaling events mediating the action of ethanol on adiponectin and its hepatic signaling. Since effects of ethanol on SIRT1 and adiponectin are highly regulated by dietary factors and pharmacological agents, these studies may lead to novel therapeutic strategies for the treatment of human AFLD and possibly steatohepatitis. PUBLIC HEALTH RELEVANCE: Adiponectin plays a vital role in the development of alcoholic fatty liver disease. This renewal application will study the molecular mechanisms by which ethanol inhibits adipose-derived adiponectin expression and impairs its hepatic signaling. This study will increase our knowledge of the pathogenesis and therapeutics for treatment of human alcoholic fatty liver disease and possibly steatohepatitis.